DESCRIPTION: Our major long term objective is to completely understand the biochemistry of methane formation which is found only in a group of unusual microbes, the Methanoarchaea. These organisms produce on this planet 10E11 kilograms of methane (the most efficient greenhouse gas) per year from anaerobic habitats such as the rumen caecum, intestine (including humans), rice paddies, sediments, and sewage sludge. We cannot predict whether the study of six unusual co-enzymes unique to the methane formation pathway will lead to chemotherapeutic insights in human disease or whether they will contribute only to a general understand of biochemistry. It is significant that one of these unusual co-enzymes, F420, has recently been found to be an electron carrier in Mycobacterium. The Methanoarchaea differ in many ways from typical bacteria. Genes for replication, transcription, and translation are very similar to yeast and humans, whereas genes for metabolic functions are similar to typical bacteria. Of the two complete genome sequences now available, about 50% to 60% of the genome represents unknown new functions. By use of new genetic techniques which we have developed for Methanosarcina, the most metabolically diverse methanoarchaeon, we intend to use our knowledge of these co-enzymes and enzymes to gain new sights into biochemistry of co- enzyme synthases, enzyme-co-enzyme control and regulation, as well as to provide knowledge about the unknown half of the genome. Another objective concerns exploratory studies on the oxidation/reduction of phosphorus in methanogenic habitats where phosphine (HSP), a highly toxic gas, has been detected in sediments, rice paddies, and the human intestine.